Microtubules are protein polymers that are involved in many physiological processes, especially mitosis and cell division, and are formed by α-tubulin and β-tubulin heterodimers. Microtubules are essential for maintaining cell shape and polarity, the intracellular transport of vesicles and organelles. During eukaryotic cell division, microtubules form mitotic spindles, which align replicated chromosomes to the equatorial plane and mediate the subsequent segregation of chromosomes to the two daughter cells [K. H. Downing, E. Nogales, Curr. Opin. Cell Biol. 1998, 10, 16-22]. These drugs interfere with the polymerization depolymerization properties of microtubules to prevent cell cycle progression, inducing the cells to undergo programmed cell death. Due to this microtubules are potential targets for the development of chemotherapeutic drugs which target rapidly dividing cancer cells [S. Honore, E. Pasquier, D. Braguer, Cell Mol. Life Sci. 2005, 62, 3039-3056]. Combretastatin A-4 (CA-4) S1 is a natural cis-stilbene that was isolated by Pettit co workers in 1989 from the South African willow tree Combretumcaffrum. Because of its structural simplicity and strong anticancer properties, CA-4 is presently one of the most promising target to develop new potential drugs for cancer. CA-4 has been found to be a potent inhibitor of tubulin polymerization, as it binds to the colchicine binding site and exerts significant cytotoxicity toward a wide range of human cancer cell lines, including multidrug-resistant cancer cells G. R. Pettit, M. R. Rhodes, D. L. Herald, E. Hamel, J. M. Schmidt, R. K. Pettit, J. Med. Chem. 2005, 48, 4087-4099]. Recently it has been reported that a new class of combretastatins such as (Z)-5-(3,5-dimethoxystyryl)-2-methoxyaniline S3 exhibit potential cell proliferation against CA-4 resistant cell lines (BMEC and HT-29) and also explained that in these (Z)-5-(3,5-dimethoxystyryl)-2-methoxyaniline inhibited tubulin polymerization five times stronger than CA-4 by binding at colchicine binding site. (Simoni D, Romagnoli R, Baruchello R, Rondanin R, Grisolia G, Eleopra M, Rizzi M, Tolomeo M, Giannini G, Alloatti D, Castorina M, Marcellini M, Pisano C, Novel A-ring and B-ring modified combretastatin A-4 (CA-4) analogues endowed with interesting cytotoxic activity, J. Med. Chem. 2008, 51, (19), 6211-6215). E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide) S4 an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of different human tumor cell lines. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth-inhibitory activity. 14C-labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR. E7010 was active against two kinds of VCR-resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, E7010 is a tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol [Yoshino, Hiroshi; Ueda, Norihiro; Niijima, Jun; Sugumi, Hiroyuki; et al. J. Med. Chem. 1992, (35), 2496-2497].

In continuation of these efforts and our interest in the structural modifications of the combretastatin A4 and E7010, we describe here in an efficient access to the construction of some new (Z)-3,4,5-trimethoxystyryl benzene sulfonamides with improved cytotoxic activity in certain cell lines.